MOLECULAR/CELLULAR BASIS OF CARDIAC ALLOGRAFT REJECTION

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The primary objectives of this research proposal are to identify the molecular components of the immune recognition process involved in allograft rejection. Graft rejection is initiated by T cells of the recipient recognizing antigens of the foreign graft through clonally- expressed TCRs. The basis of this recognition process is the formation of a trimolecular complex consisting of the TCR, MHC molecule (of the recipient and/or donor type), and a peptide derived from metabolically processed graft antigens. The formation of this complex during immune response to the graft initiates a set of intra- and intercellular reactions that result in destruction of the graft. Hence, elucidation of the nature of the trimolecular complex and the subsequent events involved in the graft rejection will not only broaden our understanding of the rejection process, but may also provide a means to induce graft- specific tolerance. The Specific Aims of this proposal include: 1. Characterization of the TCR repertoire usage by GILs isolated from cardiac allografts performed in rat strain combinations disparate for range of histocompatibility antigens. 2. Establishment of T-cell lines and/or clones from GILs with specific reactivity to graft antigens and examination of their role in mediating cardiac graft rejection following adoptive transfer. 3. Identification of graft antigens that serve as targets for graft- reactive T cells and the analysis of their role in the rejection reaction.